Process for preparing 1,3-dihydroimidazole-2-thione derivatives

Abstract

The present invention relates to a process for preparing (R)-5-(2-(benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione, and pharmaceutically acceptable salts thereof, especially the hydrochloride salt. The invention also relates to a process for making intermediates useful in the formation of said compound, and to the intermediates, per se.

What is claimed is: 
     
       1. A process for preparing a compound of formula RY or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein, R 1 , R 2  and R 3  are the same or different and signify hydrogen, halogen, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; and 
         X signifies CH 2 , an oxygen atom or a sulphur atom; 
         which process comprises deprotecting a compound of formula K 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3  and X are as hereinbefore defined in formula RY and Ns signifies o-nitrophenyisulphonyl; 
         and optionally thereafter converting the compound RY to a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The process according to  claim 1 , wherein X is O. 
     
     
       3. The process according to  claim 1 , wherein one of R 1 , R 2  and R 3  is hydrogen, and the others are fluorine. 
     
     
       4. The process according to  claim 1 , wherein compound RY has the formula RY′ 
       
         
           
           
               
               
           
         
       
     
     
       5. The process according to  claim 1 , wherein said deprotection step comprises treating a compound of formula K with thioglycolic acid in a suitable solvent, in the presence of a base. 
     
     
       6. The process according to  claim 1 , wherein the compound RY isolated from the deprotection step is purified. 
     
     
       7. The process according to  claim 5 , wherein purification is performed: via a two-step procedure comprising (i) formation of an HCl salt of a compound of formula RY and (ii) crystallisation of the HCl salt so formed from a suitable solvent; or via a re-slurry in 2-butanone. 
     
     
       8. The process according to  claim 1 , wherein the compound of formula K is prepared by reacting a compound of formula I, 
       
         
           
           
               
               
           
         
         wherein Ns signifies o-nitrophenylsulphonyl; 
         with a compound of formula JZ, 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3  and X are as hereinbefore defined in  claim 1 , X signifies X signifies CH 2 , an oxygen atom or a sulphur atom, and Z is selected from L-tartrate, hydrochloride, mesylate, tosylate, trifluotoa,cetate, citrate, glycolate and oxalate. 
       
     
     
       9. The process according to  claim 8 , wherein the compound of formula I is prepared by hydroxylating a compound of formula G, 
       
         
           
           
               
               
           
         
         wherein Ns signifies o-nitrophenylsulphonyl. 
       
     
     
       10. The process according to  claim 8 , wherein the compound of formula I is prepared by hydrolysing a compound of formula H, 
       
         
           
           
               
               
           
         
         wherein Ns signifies o-nitrophenylsulphonyl. 
       
     
     
       11. The process according to  claim 10 , wherein the compound of formula H is prepared by acylating a compound of formula G, 
       
         
           
           
               
               
           
         
         wherein Ns signifies o-nitrophenylsulphonyl. 
       
     
     
       12. A process according to  claim 9 , wherein the compound of formula G is prepared by brominating a compound of formula F, 
       
         
           
           
               
               
           
         
         wherein Ns signifies o-nitrophenylsulphonyl. 
       
     
     
       13. The process according to  claim 12 , wherein the bromination of compound F is achieved using Br 2 . 
     
     
       14. The process according to  claim 12 , wherein the compound of formula F is prepared by reacting a compound of formula E, 
       
         
           
           
               
               
           
         
         with o-nitrophenylsuplonyl chloride. 
       
     
     
       15. The process according to  claim 14 , wherein the conversion of compound E to compound F is carried out in the presence of a suitable base, preferably triethylamine, and a catalytic amount of a suitable alkali metal alkoxide. 
     
     
       16. The process for preparing a compound of formula RY or a pharmaceutically acceptable salt thereof according to  claim 1 , the process comprising converting benzylamine E to a compound of formula F in the presence of o-nitrophenylsulphonyl chloride and methyl vinyl ketone (MVK); brominating the compound F to a compound of formula G; hydroxylation of compound G to a compound of formula I or acetylating compound G to form a compound of formula H followed by hydrolysing the compound H to form a compound of formula I; reacting the compound I with a compound of formula JZ to form a compound of formula K; and deprotecting compound K to form compound RY, and optionally converting compound RY to a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein Ns is o-nitrophenylsulphonyl, and R 1 , R 2 , R 3  and X are as defined in  claim 1 . 
       
     
     
       17. The process according to  claim 5 , wherein the base is LiOH or KOH. 
     
     
       18. The process according to  claim 7 , wherein the suitable solvent is toluene. 
     
     
       19. The process according to  claim 15 , wherein the suitable alkali metal alkoxide is t-BuOK.